Following exposure to traumatic stress individuals often go on to develop Post-Traumatic Stress Disorder (PTSD), which is characterized by enhanced anxiety to reminders of the trauma, nightmares, reliving the traumatic experience and a propensity to acquire new fears. PTSD is characterized by excessive drinking, anxiety, and depression that lasts for a prolonged period after the initial trauma. The result is that PTSD has a significant impact on the lives of individuals as well as on society as a whole. One challenge is to find the common link between stress-induced changes in anxiety, alcohol intake and depression. Considerable data suggest that neuroimmune factors may be that link. Once thought to be merely the packing peanuts of the brain, glial cells in the brain and spinal cord are integral to the proper functioning, signaling, and neuronal reparation in the brain. Microglia specifically are involved in neuroinflammation, which is associated with destructive chronic neuroimmune response. Activation of microgila produces pro-inflammatory cytokines. Increases in levels of pro-inflammatory cytokines are observed in PTSD, and major depressive disorder (MDD). Microglia as well as pro-inflammatory cytokines are increased in the brains of alcoholics. Thus, neuroimmune factors lay at a nexus of PTSD, depression and alcoholism. It is not known what mediates these long-term stress-induced changes, but stress can produce a neuroimmune response that significantly alters behavior. To address this challenge, we have assembled a team with demonstrated expertise in emotion related behavior (Fanselow), stress-induced neuroimmune function (Bradesi &Mayer), and the neurobiology of alcohol (Spigelman). Using a behavioral model of PTSD, our aims are to determine if stress is associated with a neuroimmune response within the amygdala and to determine if this response predicts changes in behavior, as well as determine if blockade of glia activation/neuroimmune response will reverse the behavioral sequelae of stress. Preliminary data with this stress model indicates exaggerated reactions to novel startling stimuli, increased anxiety and enhanced learning of new fears, which persist at least 3 months after stress without diminution. The same stress increased voluntary alcohol consumption relative to an unstressed control group. The model also produces prolonged alterations in gene expression patterns in the amygdala with up-regulation of several genes related to cytokines. Although stress-induced activation of central nervous system pro- inflammatory responses have been reported, there are significant gaps in knowledge about how they contribute to long term emotional disturbances and influence the amygdala. PUBLIC HEALTH RELEVANCE: Post-Traumatic Stress Disorder is characterized by excessive drinking, anxiety, and depression that develop and last for a prolonged period after the initial trauma. We will test the hypothesis that neuroimmune factors, such as cytokines and chemokines released in the CNS that are activated by stress mediate these long-lasting changes in behavior by acting like neurotransmitters, neuromodulators, or neurohormones in the brain. We will also determine if pharmacologically interfering with these neuroimmune pathways mitigate the symptoms of PTSD.